Diesters of 2, 5-dihydroxyhexanedinitrile with carboxylic acids



United States Patent 3,331,864 Patented July 18, 1967 s 331 864 DIESTERS F asbmirnnoxnmxmm- NITRILE WITH CARBOXYLIC ACIDS ON ON KCN l I 1328 OOHCHzCHzCHO m RCOOCHCHzCI-IzCHOOCR Miklos Bodanszky, Princeton, and John T. Sheehan, (R O OMO Middlesex, N.J., assignors, by mesne assignments, 5 A to E. R. Squibb & Sons, Inc., New York, N.Y., I Rzphenyl a corporation of Delaware No Drawing. Application June 29, 1962, Ser. No. 206,155, i H

now Patent N2. 3,2g1fh57, eatedfiAug1.3%7&91596s5, while; X CH COOOOR is a division 0 a ca on er. 0. e a 1961, now Patent i 10. 3,065,240, dated rsdv. 20, 1962: RCOOCHCHICECHOOCR which in turn is a division of application Scr. No. B 47,129, Aug. 3, 1960, now Patent N0. 3,040,054, dated 1 nd 1 9, 1962. I5)ivided and this application Mar. 4, 11 LWDY 1 64 er. N0. 3 5 42 2 Claims. (Cl. 260-465) 15 f l jgi This application is a division of our application, Ser. E? i EE KOH No. 206,155, filed June 29, 1962, now Patent No. 3,201,- ROOCC-N l l'CCOOR 457, which in turn is a division of our application, Ser. 0 No. 137,495, filed Sept. 12, 1961, now Patent No. 3,065,- 111 R=pheny1; 240 which in turn is a division of our application, Ser. No. 47,129, filed Aug. 3, 1960 and now Patent No. 3,040, 8 F E s 054, granted June 19, 1962. CHCHzCH2CH- Nmono, This invention relates to new chemical corn-pounds and I more particularly to a new thiazolecarboxylic acid of the H 0 N N 00 formula IV NHz NH2 0 0 s s s u s mazncrnornonh/ I I WV CH2CH2C/ H HGOONH; HOOCJL COOH HOOC N Iii COOH and salts thereof. Since the thiazolecarboxylic acid con- X NH tains both basic (i.e. amino) groups and carboxylic acid S I 2 1 a 5 groups it is amphoteric in nature and thus forms salts I TOHCHQCHR-CH with acids and bases. Although any acid or base may be i i J i used in preparing the salts, the preferred acids are min- H000 COOH eral acids, such as the hydrohalic acids (e.-g., hydro- VI chloric and hydrobromic acid), sulfuric acid, nitric acid To prepare Compounds A succinaldehyde is interacted and PhPSPhOIiC acid The prefgrfed bases are ammonium with a cyanide, such as an alkali metal cyanide (e.g., pohydroxide, alkali metal hydroxides -(e.g., potassium hy tassium cyanide) and an acylating aoent of either the droxide and sodium hydroxide) and alkaline earth metal formula RCOX (RCO)2O WhereinR vis as hereinhe hYFmXideS i h 'aFldition organic fore defined, and X is a halide, preferably chloride. The acids such as tartaric, citric and acetic acid, and organic reaction conducted in an aqueous medium preferably bases Such as,alkylamldes f in the cold, and results in the preparation of the two iso- The new thiazolecarboxyhc acid of this invention (as mars f h .diegte-IS f 2,5-dihydroxyheXanedinitrile. Well as its salts) is useful as a precursor in the microbial Compounds A the acid moiety of the ester correspond preparation of the antibiotic thiostrepton. For this purinc to the acyiafino aoent used pose it is added at a concentration greater than about prepare i f B either of the isomers of 0.001% (w./v.) to a nutrient medium containing a compound A is treated h hydrogen sulfide 1she Source of carbon and f f a source of asslmllable action preferably being conducted under basic conditions. Source of assl'mllable Sulfur (such as that f The reaction results in the preparation of Compounds B, Embed m US Patent 2982,6891 when culnfrmg the diesters of 2,5-dihydroxydithiohexanediamide, where- Streptomcyes azm'eus (Waksman Collection No. 3,705, Inin the acid moiety of the ester corresponds to the acy1at stitute of Microbiology, New Brunswick, NJ.) for the prom agent used in the first step of the Process ductlon of thlos't'repton' Compounds B are then condensed with an ester of halolhe final products of this invention are prepared by a pyl-uvic acid of the formula; X'CHzCOCOOR', wherein series of reactions using as the initial reactants succinis halo, Preferably bromo, and is as hereinbefore aldehyde rerflcnons are shown sFhematlfliauy by defined. The reaction is preferably conducted in an organic the followmg ,equatlons- In these equations, R 15 a solvent at an elevated temperature, such as the reflux drocarbon radical of less than ten carbon atoms, such as temperature of the Solvent and results in the preparation lower alkyl (e.g., methyl, ethyl, propyl, butyl and hexyl) of Compounds C, wherein R and R are as hereinbefore aryl (e.g., phenyl, p-tolyl and o,p-Xylyl), aralkyl (e.g., d fi d y Phenethyl and -P Y 'P PY and Wcloalkyl Compounds C are then hydrolyzed in the usual manner, w cyclopentyl and cyclohexyl); and is Saturated as by treatment with a base, such as an alkali metal hyhydrocarbon radical of less than ten carbon atoms, such d id (e potassium hydroxide) to yield Compound as lower alkyl methyl, y P PY and S/U- IV, 2,2 (1,4-dihydroxytetramethylene)bis-(4-thiazole- Each of the intermediates formed is a new compound carboxylic acid). of this invention. In addition to their use as intermedi- Compound IV is then oxidized by treatment with sodiates, Compounds IV and V can also he used as precursors in the production of thiostrepton.

um dichromate to give Compound V, 2,2-succiny1bis(4- thiazolecarboxylic acid).

EXAMPLE 1 Benzoic acid, diester with 2,5-dihydrxyhcxancdinitrile (I) A mixture of 30 g. of succinaldehyde, 750 g. of cracked ice, 44 g. of potassium cyanide and 94 g. (78 ml.) of benzoyl chloride is stirred for 1 hour. A milky semisolid separates -from the reaction mixture. The mixture is filtered by suction, and the white solid residue washed with water to give on drying about 15 g. solid 1. The original filtrate of the reaction mixture is extracted four times with 250 ml. portions of chloroform and the combined chloroform extract washed first with a solution containing 60 g. of sodium bicarbonate in 750 ml. of Water and finally with three portions of 250 ml. of water. The chloroform extract is dried over anhydrous magnesium sulfate and after removing the latter and evaporating the solvent a residue of about 62 g. of heavy liquid remained. This residue on treatment with several volumes of hexane gives about 19 g. of solid 11.

Solids I and II are separately treated with ether, from which extracts benzoic acid is recovered. The ether insoluble materials are treated with toluene on the steam bath and from these extracts a material, M.P. about 134136, separates.

Analysis.Calcd for C H N O C, 68.96; H, 4.63; N, 8.04. Found: C, 68.89; H, 4.60; N, 7.93.

The toluene materials are then treated with dimethylformamide on the steam both and solution is complete. On cooling a crystalline product melting at about 214 216 separates.

Anaiysis.Found: C, 68.96; H, 4.81; N, 8.10.

The infrared spectra of both compounds are substantially the same.

EXAMPLE 2 Benzoic acid, diester with 2,5-dihydr0xy-dithi0hexanediamide (II) In to a solution of 4.6 g. of the lower melting dinitrile obtained in Example 1 in 25 ml. of dimethylformamide containing 0.3 ml. of triethanolamine is bubbled hydrogen sulfide for six hours. After the addition of gas, the stoppered mixture is allowed to stand for 24 hours. The mixture is then treated with hexane and enough ethanol to make the mixture homogeneous. On standing :1 yellow solid slowly separates. Ultimately with scratching and further diluting with hexane and ethanol about 5 g. of product is'obtained. The product is crystallized from large volumes of boiling ethanol and melts at about 203- 205 Analysis.Calcd for C H N O S N, 6.73; S, 15.37. Found: N, 6.94; S, 15.40.

EXAMPLE 3 2,2- (1,4-dihydroxytetramethylene) bis(4-thiaz0lecarb0xylic acid diethyl ester, diester with benzoz'c acid) (H!) A mixture of 2.5 g. of the dithioamide obtained in Example 2 and 2.5 g. of ethylbromopyruvate in 100 ml. of ethanol is heated under reflux for one and one-half hours on the steam bath. On cooling a solid separates. The solid is filtered oft" to yield about 2.9 g. of solid, which is crystallized from 100 ml. of boiling ethanol. The product melts at aboufil4 r145".

Analysis.Calcd for C H N O S N, 4.60; S, 10.52. Found: N, 4.68; S, 10.61.

EXAMPLE 4 2,2'- (Z,4-dilzydroxytetramethylene) bis(4-tlziazolecarboxylic acid) (IV) 2.1 g. of the ester obtained in Example 3 is suspended in 50 ml. of absolute ethanol and 0.76 g. of potassium hydroxide in 5 m1. of absolute ethanol is added. While stirring at room temperature solution occurs within onehalf hour. The mixture is allowed to stand at room temperature overnight during which time a solid separates out. The insoluble material is filtered off and Washedwith ethanol. it is dissolved in 10 ml. of water and the aqueous solution then washed with ether and then acidified with 1 N hydrochloric acid. From the acid solution a recipitate slowly formed which is filtered off, washed with water, and air dried to give about 1.0 g. of product, Ml. about 235440". From the original mother liquor on evaporation a residue of about 1.6 g. of product is obtained.

The residue is dissolved in 10 ml. of water and after Washing the aqueous solution with ether, the aqueous solution is acidified with hydrochloric acid and the precipitate which forms filtered oif. This material is benzoic acid. From this and the previous acid solution however, on cooling and standing about 0.2 g; additional product separates. Crystallized from boiling water, this compound separates out with one mole of water of crystallization which is lost on drying at The compound, 2,2- (1,4 dihydroxytetramethylene)bis(4-thiazolecarboxylic acid) melts at about 240245 (dec.).

AItalysis.Ca1cd for C H N O S C, H, Found: C, 42.01; H, 3.95.

EXAMPLE 5 2,2'-succiayl bis(4-tlziaz0lecarboxylic acid) (V) 600 mg. of the diol acid obtained in Example 4 is suspended in 15 ml. of glacial acetic acid distilled from chromium trioxide, and 500 mg. of sodium dichromate in one-half a cubic centimeter of water is added to the suspension. The Whole is kept at 100 for 2 hours. On cooling an insoluble material settles out. This material is filtered OE and washed with a large amount of Water and some dilute acetic acid. It weighs about 400 mg. After crystallization from dimethylformamide the 2,2-succinyl bis(4-thiazolecarboxylic acid) has a Ml. of about 284- 286 (dec.).

Ana!ysis.Calcd for C H N O S C, 42.36; H, 2.37. Found: C, 42.52; H, 2.90.

EXAMPLE 6 2,2-(1,4-diaminotetramethylene)bis-(4-thiaz0lecarboxylic acid) (VI) 100 mg. of the dilteto acid obtained in Example 5 is intimately mixed with 2.0 g. of ammonium formate in a Ciaisen type distilling flask. The flask is heated in an oil bath at an internal temperature of -155 until the initial foaming reaction subsides. The internal temperature is then gradually raised to -190 where it is kept for 3 hours. On cooling the residue is taken up in 25 ml. of water and any insoluble material'removed via filtration.

The filtrate is acidified with hydrochloric acid whereupon a precipitate separates out. It is filtered off and washed with water to yield a mixture of formyl derivatives. This mixture is heated under reflux with 5 ml. of concentrated hydrochloric acid for an hour. Hydrolysis proceeds and the mixture becomes homogeneous. On evaporation the residue obtained is dissolved in water from which VI slowly separates. It melts at about 235-237 (dec.). Caicd for C l-I O N S C, 42.1; H, 4.12; N, 16.4; S, 18.7. Found: C, 42.5; H, 4.29; N, 16.4; S, 18.8. On Whatman No. 1 paper in a system of n-butanol-acetic acid-water (4:1:1) the acid movesfaster than cystine, RE 0008-010.

5 EXAMPLE 7 2,2'- (1,4-diamin0tetramethylene) bis(4-thiaz0lecarboxylic acid) dihydrochloride 40 mg. of 2,2-(1,4-diaminotetramethy1ene)bis(4-thia- 5 zolecarboxylic acid) is dissolved in warm N-hydrochloric acid. The dihydrochloride salt which forms slowly separates from solution and is removed by filtration.

EXAMPLE 8 2,2- (1,4-diaminotetramethylene) bis(4-thiaz0lecarboxylic acid), ammonium salt The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. The diester of 2,S-dihydroxyhexanedinitrile with a hydrocarbon carboxylic acid of less than ten carbon atoms selected from the group consisting of lower alkyl, aryl, aralkyl and cycloalkyl.

2. The diester of 2,5-dihydroxyhexanedinitrile with benzoic acid.

References Cited UNITED STATES PATENTS 2,759,963 8/1956 Blair 260465 CHARLES B. PARKER, Primary Examiner.

DOLPH H. TORRENCE, Assistant Examiner. 

1. THE DIESTER OF 2,5-DIHYDROXYHEXANEDINITRILE WITH A HYDROCARBON CARBOXYLIC ACID OF LESS THAN TEN CARBON ATOMS SELECTED FROM THE GROUP CONSISTING OF LOWER ALKYL, ARYL, ARALKYL AND CYCLOALKYL. 